This program project is intended to serve as a combination of the applicant and his team's basic and clinical research in the use of radiolabeled antibodies for cancer therapy (radioimmunotherapy, or RAIT), supported by a NIH Outstanding Investigator Grant for two 7-year periods. The current grant will include 1 laboratory and 3 clinical research projects, as well as core laboratories addressing the common theme of developing and investigating these biological imaging and therapy agents in 3 cancer types of an endocrine nature; namely, mammary, ovary, and medullary thyroid cancers. Each cancer type will be investigated in terms of better therapy methods, the latter in combinations with chemotherapeutics of current clinical interest. The overall long-term objectives are to define the role of radioimmunotherapy in a multimodal treatment program. Specifically, the P01 will comprise: Project 1: Rational Design of Chemo- and Radioantibody Therapy (evaluate the role of multimodality, chemotherapy and RAIT, the effects on molecular markers, especially in isolated human tumor cells from patient blood samples having drug and apoptotic markers); Project 2: Radioimmunotherapy of Stage IV Breast Cancer (evaluate three Phase I trials that combine 90Y-hMN014 anti-CEA with conventional chemotherapy in the treatment of Stge IV breast cancer and assess 2 new murine antibodies against MUC-1 and EGP-1 for therapy applications); Project 3: Radioimmunotherapy of Epithelial Ovarian Cancer (evaluate the role of RAIT in combination with chemotherapy in the treatment of ovarian cancer patients who have failed standard therapy, including marrow grafting, for advanced disease, as well as evaluate antibodies to MUC-1 and EGP-1); Project 4: Radioimmunotherapy of Medullary Thyroid Cancer (evaluate the role of RAIT alone and in combination with chemotherapy in the treatment of this orphan cancer type in Phase I/II trials); Core Laboratories/Units; A. Antibody Production, QC, and Reengineering; B. Radiolabeling (Clinical and Experimental); C. Animal Experimentation; D. Histology Laboratory; E. Dosimetry, and F. Administration, Project Management, Regulatory and Statistical Units.